The long-term objective of this proposal is to understand how addictive drugs "hijack" brain circuits involved in the association of neutral environmental stimuli with reward. Psychostimulants such as amphetamine are thought to cause excessive dopamine release from mesolimbic neurons originating in the ventral tegmental area, which in turn would activate the nucleus accumbens to ventral pallidum reward circuit. Increased dopamine and associated circuit changes may underlie a pathological state in which reward-associated cues become overly attractive and cause excessive "wanting" of reward. Goals of the current proposal will be to identify, as well as compare and contrast, brain regions critical for mesolimbic dopamine release to enable reward-related cues to activate ventral pallidal neurons. Mesolimbic dopamine contributions to the ability of amphetamine to strengthen cue-induced increases in ventral pallidal firing rates and recruit larger responsive populations of ventral pallidal cells will also be evaluated. Dopamine neuronal projections from the ventral tegmental area to the nucleus accumbens and the ventral pallidum are hypothesized to be crucial for reward-related cues to activate ventral pallidal neurons, and for amphetamine to enhance the potency of cues on reward-related ventral pallidal firing. We will lesion dopamine neurons with 6- hydroxydopamine (6-OHDA) in the ventral tegmental area (Aim 1), nucleus accumbens (Aim 2), or ventral pallidum (Aim 3). After recovery, extracellular recordings of ventral pallidal neurons will be obtained in awake, behaving rats that are presented with previously learned reward (intraoral sucrose)-associated cues. Under vehicle and amphetamine conditions, firing rates before and after the cues and the sizes of responsive neural populations for dopamine-depleted rats will be compared to rats with sham lesions. 6- OHDA lesions of each region are expected disrupt or completely block cue-elicited activation of these neurons. Whether both pathways are necessary or if one can compensate for the loss of the other will be tested. This research will provide insight into information processing in brain circuits essential for reward, and importantly, how information reward-related neural processing might be disturbed by addictive drugs. Such information will be useful for understanding addiction and developing new therapies for treatment.